PROJECT SUMMARY/ABSTRACT Recent research has identified a strong association between Campylobacter and chronic malnutrition, evidenced by linear growth faltering, in children in low-resource settings. However, the importance of individual Campylobacter species and the mechanism underlying this association have not been defined. Meanwhile, comprehensive water, sanitation, and hygiene (WASH) interventions have failed to improve linear growth or even to reduce Campylobacter prevalence. A better understanding of the epidemiology and burden of Campylobacter infections as well as the reservoirs and pathways for exposure to diverse Campylobacter infections is needed to guide next-generation WASH studies and other interventions to reduce stunting, and the specific pathways underlying the association between Campylobacter and poor linear growth need to be identified. Our group has pioneered the application of quantitative molecular diagnostics for a broad range of pathogens to studies of diarrhea etiology and the impact of enteric infections on growth. These studies have revealed the limitations of bacterial culture, which has obscured characterization of the prevalence and importance of diverse Campylobacter species. We have developed a high-throughput, culture-independent diagnostic approach using targeted long-read next generation sequencing, which reveals a broad diversity of Campylobacter species in children in these settings, including a strikingly high prevalence of C. hyointestinalis, more than twice as prevalent as C. jeuni in our birth cohort in Tanzania. In Aim 1, we will apply this diagnostic approach to describe the epidemiology and impact of Campylobacter species in children in three low-resource settings, using previously archived DNA from stool samples collected from the multisite MAL-ED birth cohort study in Loreto, Peru, Dhaka, Bangladesh, and Haydom, Tanzania. This will establish the species-specific prevalence, species-specific attributable incidence of diarrhea, risk factors, and association with poor linear growth. In Aim 2, we will characterize Campylobacter species infections in a larger birth cohort in Haydom, Tanzania to validate the associations with growth identified in Aim 1 and to define mechanisms underlying these associations. We will specifically test the hypothesis that impaired gut motility driven by an immune response to cytolethal distending toxin B and associated small intestinal bacterial overgrowth is associated with poor linear growth. We will define the relative importance of this mechanism compared to other possible pathways. In Aim 3, we will establish a transmission cohort in Haydom, Tanzania to understand the major reservoirs of and pathways for Campylobacter infections in this rural African setting. In total, this work will establish the